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Selenoprotein biosynthesis is mediated by tRNA^Sec, which inserts selenocysteine at UGA codons in a complex, context-specific manner. This opal suppressor serves in the conversion of serine to selenocysteine as well. The mouse tRNA^Sec gene (Trsp) maps to a proximal segment of chromosome 7. We constructed mice carrying a targeted deletion of the Trsp gene. The heterozygous mutants were viable, fertile, and appeared normal. Although the level of tRNA^Sec was reduced to about 50%–80% of the wild type in most organs, one of the selenoproteins, glutathione peroxidase, remained unaffected in the levels of its mRNA, protein, and enzyme activity, indicating that the haploid amount of tRNA^Sec is not limiting in its biosynthesis. In contrast, the homozygous mutants died shortly after implantation, and the embryos were resorbed before 6.5 days post coitum. When the preimplantation embryos were placed in …